rs137852557

Positions:

chrX-640836-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PS1PM1PM5PP3_StrongPP5_ModerateBS2

The NM_000451.4(SHOX):c.502C>T(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. 3 hem. )

Consequence

SHOX
NM_000451.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 0.883

Variant links:

Genes affected

SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

SHOX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1

Transcript NM_000451.4 (SHOX) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 9879

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000451.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-640837-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3344829.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant X-640836-C-T is Pathogenic according to our data. Variant chrX-640836-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9879.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-640836-C-T is described in Lovd as [Pathogenic].

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	3/5	ENST00000686671.1
SHOX	NM_006883.2 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	3/5		NM_000451.4	P1	O15266-1
SHOX	ENST00000381575.6 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	3/5	1			O15266-2
SHOX	ENST00000381578.6 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	4/6	5		P1	O15266-1
SHOX	ENST00000334060.8 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	4/6	5			O15266-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251180

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Leri-Weill dyschondrosteosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Langer mesomelic dysplasia syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2024

Identified in individuals with SHOX-related disorders in the published literature (PMID: 23636926, 15356038, 15931687, 11889214); Published functional studies suggest that this variant leads to a loss of DNA binding and reduced ability for homodimer formation (PMID: 15931687); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23636926, 15931687, 15356038, 32932528, 21262861, 11889214) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.92

D;D;.

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.7

H;H;H

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.85

MutPred

0.87

Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);Loss of disorder (P = 0.0332);

MVP

1.0

MPC

1.6

ClinPred

0.99

GERP RS

0.30

Varity_R

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over